Magnetic resonance imaging and spectroscopy are extensively used as diagnostic and research tools. Their use is widespread, in part because the methods are non-invasive and in human studies do not necessitate the exposure of the patient to potentially harmful radiation such as X-rays.
Magnetic resonance spectroscopy is widely used as an analytical tool for the investigation of molecular structure, dynamics, and metabolism, both in vitro and in vivo. Conventional MRI is based largely on the detection of signals from water, and from fats also, and has widespread applications in biomedical research and diagnostic radiology. While these techniques are very powerful, they would be even more powerful if fuller use could be made of the potential nuclear magnetism of the compounds being detected.
Magnetic resonance signal strength is partly dependent on the population difference between the nuclear spin states of the imaging nuclei, i.e. the difference between the populations of nuclear magnets aligned with and against an applied magnetic field. This difference is governed by the Boltzmann distribution.
Under thermal equilibrium conditions (for example at room or body temperature), the nuclear magnets aligned against the field have slightly higher energy than those aligned with it, and will as a result have a slightly smaller population. Because the population difference between the two states is very small, the nuclear magnetism is said to be weakly polarised (typically of the order of 0.01-0.001%).
In the case of proton MR, the weak level of polarisation has the effect that only a tiny proportion (typically of the order of 1 in 10,000-100,000) of the protons (for example in water) are detected, and the proportions are even smaller for other nuclei such as 13C, 15N, and 31P. There is therefore considerable interest in increasing this polarisation in order to enhance the overall sensitivity of the technique.
One approach is to increase the field strength, but there are constraints on providing ever more powerful magnets as well as potential ill effects for human studies. An alternative approach is to create an artificial, non-equilibrium distribution of the spin states of the nuclei; this may be described as the ‘hyperpolarised’ state.
Various hyperpolarisation methods applicable to 13C nuclei are reviewed in Golman et al. (Eur. Radiol. 16, 57-67, 2006). One such method is the so-called ‘brute force’ approach wherein a sample is subjected to a very strong magnetic field at very low temperature. However, Golman concludes that for 13C applications, this would require impractically low temperatures to be useful.
An analogous approach was taken by Honig in U.S. Pat. No. 6,125,654. The patent discloses a method of producing bulk hyperpolarised 129Xe using a ‘brute force’ approach, wherein the 129Xe is exposed to low temperature (e.g. 5-10 mK) and a high magnetic field (˜10 T) to increase the polarisation level. However, the time required to reach a useful polarisation level (characterised by the spin-lattice relaxation time T1) is inherently extremely long at low temperatures and high magnetic fields for spin ½ nuclei and thus in order to make the relaxation time practicable, Honig discloses the use of various ‘relaxation switches’.
According to Honig, the first requirement of a relaxation switch is that it must provide for a decrease in the relaxation time T1. The second requirement is that the relaxation switch must be removable so that when the xenon is removed from the low temperature and high field environment, the high polarisation level is not lost. Examples of suitable relaxation switches disclosed by Honig include: paramagnetic oxygen molecules, dispersed magnetized small particles encapsulated in polymers, stable free radicals, photosensitive molecules such as HI and HBr, o-H2 and HD, impurities induced via irradiation and fixed magnetic wires.
A different approach was taken in Axelsson et al. (US 2002/0058869) where the spin refrigeration technique was employed. This technique involves doping the material to be polarised with paramagnetic ions and then placing the mixture in a strong magnetic field at low temperature and repeatedly or continuously re-orienting the material relative to the magnetic field. The technique disclosed in Axelsson requires that the material to be polarised is present in the solid state and preferably in the form of a single crystal. It is also taught that it is desirable that as great a proportion of the paramagnetic ions as possible should be separated from the MR imaging agent after hyperpolarisation, in order to improve physiological tolerability and to lengthen T1, i.e. to prevent the rapid loss of hyperpolarisation once the spin refrigeration process has been completed.
A further method is the dynamic nuclear polarisation (DNP) method, see Golman et al. (Eur. Radiol. 16, 57-67, 2006). Under moderately low temperature and magnetic field conditions (e.g. 1 K and 3 T) the 13C nuclear polarisation is below 0.1%, whereas the electrons are polarised to >90%. The DNP method relies on the transfer of the high polarisation of electron spins to coupled nuclear spins. This is achieved via microwave irradiation near the electron resonance frequency. The transfer is facilitated by doping the material to be hyperpolarised with a substance containing unpaired electrons. Most paramagnetic substances may be used as DNP agents (see WO 98/58272) e.g. transition metal ions and organic free radicals such as nitroxide radicals and trityl radicals. DNP can result in an increase in the level of nuclear polarisation in an imaging agent to 20-40% or more. However, the paramagnetic agents may be toxic and may require removal before injection of the hyperpolarised material into the body.
Herein, and elsewhere in the art, the term ‘hyperpolarisation’ is used to mean having a greater degree of polarisation than at equilibrium under typical magnetic resonance operating conditions (for example at room temperature and in a magnetic field of up to ˜20 T). Thus a sample is also described as hyperpolarised when it is at a low temperature and in a high magnetic field so long as the degree of polarisation is higher than it would be at equilibrium at room temperature and in a magnetic field of up to ˜20 T, even though the polarisation of the sample may in fact be at thermodynamic equilibrium under the applied high magnetic field and low temperature conditions.
While the methods described above go some way towards providing effective hyperpolarisation of agents for MRI and MRS, there remains a need for further, more effective methods of hyperpolarisation.